The present invention relates to a novel antimicrobial peptide and more particularly to an antimicrobial peptide which is a partial peptide of a human-derived antimicrobial protein, in which amino acid residues thereof are partially substituted. Also, the present invention relates to an antimicrobial agent as well as a medicine such as a bacterial infection-treating agent and an endotoxin shock suppressant, each comprising the antimicrobial peptide as an active ingredient. Further, the present invention relates to an endotoxin-removing agent comprising the antimicrobial peptide immobilized on an insoluble carrier.
CAP18 (Cationic antimicrobial protein of 18 kDa) is an antimicrobial protein found in human and rabbit granulocytes.
Japanese Patent Application Laid-open No. 8-504085 (1996) describes the whole amino acid sequence of human-derived CAP18 inclusive of its signal peptide portion. Also, it describes a partial peptide comprising C-terminal 37 amino acid residues of the human-derived CAP18 having an amino acid sequence in which a sequence derived from a rabbit is substituted for a portion thereof.
MINOPHAGEN MEDICAL REVIEW, Vol. 43, No. 1, pp. 1-15 (1998) describes the whole amino acid sequence of human-derived CAP18. It also describes partial peptides comprising C-terminal 34, 32, 30, 27, 24 and 22 amino acids residues, respectively, of the human-derived CAP18. Also, it shows data on the antimicrobial activities of these peptides on Escherichia coli, Salmonella, methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA).
GENDAI IRYO (Current Medical Treatment), vol. 28 (special number III), pp. 2367-2375 (1996) describes the whole amino acid sequence of human-derived CAP18. It also describes partial peptides comprising C-terminal 34, 30, 27, 24 and 22 amino acids residues, respectively, of the human-derived CAP18. Also, it describes data on inhibition of the lipopolysaccharide (LPS; also referred to as endotoxin) activity by these peptides.
SHOCK; From Molecular and Cellular Level to Whole Body (Proceedings of the Third International Shock Congress-Shock '95, Hamamatsu, Japan, Oct. 21-23 1995), Okada, K., Ogata, H. eds. Elsevier Science B.V., pp.109-115, (1996) describes the whole amino acid sequence of human-derived CAP18. It also describes partial peptides comprising C-terminal 34, 30, 27 and 24 amino acids residues, respectively, of the human-derived CAP18. Also, it describes data on binding activities of these peptides to LPS.
Bacterial Endotoxins; Lipopolysaccharides From Genes to Therapy. Levin, J., Alving, C. R., Munford, R. S., Redl, H. eds. Wiley-Liss, Inc., New York, pp. 317-326, (1995) describes partial peptides comprising C-terminal 37 and 32 amino acids residues, respectively, of human-derived CAP18. Also, it describes data on the influences of these peptides on production of a tissue factor by LPS, on suppression of lethality due to endotoxin shock, and on an antimicrobial activity.
However, none of the above-described publications describes or suggests those peptides with substitution of another specified amino acid residue or residues for an amino acid residue or residues at specified position or positions in the portion common to the known partial peptides of CAP18. None of them describes or suggests that such partial peptides with the substitution of the specified amino acid residue or residues have an LPS-binding activity, an antimicrobial activity, and an LPS-neutralizing activity which are remarkably higher than those of the known partial peptides.
If a peptide which is derived from human and has a high LPS-binding activity, a high antimicrobial activity and a high LPS-neutralizing activity is obtained, then there can be provided at extremely low cost an antimicrobial agent, a bacterial infection-treating agent, an endotoxin shock suppressant, and the like which are safe to humans.
The present invention has been made from the above-described viewpoints, and its object is to provide a human-derived peptide having a high LPS-binding activity, a high antimicrobial activity and a high LPS-neutralizing activity and an antimicrobial agent, a bacterial infection-treating agent, an endotoxin shock suppressant, an endotoxin-removing agent, and the like which comprise the peptide as an active ingredient.